Reductive Stress: New Insights in Physiology and Drug Tolerance of<i>Mycobacterium</i>

Mavi, Parminder Singh; Singh, Shweta; Kumar, Ashwani

doi:10.1089/ars.2019.7867

Cited by 35 publications

(44 citation statements)

References 152 publications

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“…Excess reactive oxygen species (ROS) or reducing equivalents can directly influence normal development and lead to pathologies (Grek and Townsend, 2014;Perez-Torres et al, 2017). As an inverse imbalance of oxidative stress, reductive stress (an excess of reducing equivalents), has emerged as an essential physiological parameter in both pro-and eukaryotes (Rajasekaran et al, 2007;Mavi et al, 2020). While the condition is characterized by elevated intracellular reducing equivalents, conversely by impacting mitochondrial functions and/or accumulating misfolding proteins in the ER (Peris et al, 2019;Wu et al, 2019), it can cause release of ROS, which can then activate Nrf2 (Guang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Glutathione S-Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish

Zhang

Kim

Park

et al. 2021

J Pharmacol Exp Ther

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ANOVA, analysis of variance; atf, activating transcription factor 4; atf6, activating transcription factor 6; baxb, Bcl2 associated x b; bida, BH3-interacting domain death agonist a; bim, Bcl2 interacting mediator of cell death; bip: binding immunoglobulin protein; BMDDCs, bone marrow-derived dendritic cells; CDNB, 1-Chloro-2,4-dinitrobenzene; dnajc3, DnaJ homolog subfamily C member 3; ddit3 (chop), DNA damage-inducible transcript 3; DLAR, Division of laboratory animal resources; dpf, day post fertilization; edem1, ER degradation-enhancing alpha-mannosidase-like 1; ER, This article has not been copyedited and formatted. The final version may differ from this version.

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Section: Introductionmentioning

confidence: 99%

Glutathione S-Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish

Zhang

Kim

Park

et al. 2021

J Pharmacol Exp Ther

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“…Importantly, under oxygen limiting conditions and upon inhibition of respiration, NADH levels are tremendously reduced along with lower levels of ATP (Watanabe et al, 2011;Bhat et al, 2016). Reoxidation of NADH is critical for mycobacterial cells to deter reductive stress and survive during such conditions (Mavi et al, 2020). Mycobacterium alters its ETC and central metabolic pathways to endure low levels of oxygen.…”

Section: Alternative Respiratory Complexesmentioning

confidence: 99%

“…Inhibition of respiration leads to the accumulation of NADH (Bhat et al, 2016). Accumulated NADH ultimately leads to oxidative stress (Mavi et al, 2020), and thus it is prudent for mycobacterial cells to modulate its respiration and metabolism to re-oxidize NADH.…”

Section: Nitrate Reductasementioning

confidence: 99%

Terminal Respiratory Oxidases: A Targetables Vulnerability of Mycobacterial Bioenergetics?

Bajeli

Baid

Kaur

et al. 2020

Front. Cell. Infect. Microbiol.

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Recently, ATP synthase inhibitor Bedaquiline was approved for the treatment of multi-drug resistant tuberculosis emphasizing the importance of oxidative phosphorylation for the survival of mycobacteria. ATP synthesis is primarily dependent on the generation of proton motive force through the electron transport chain in mycobacteria. The mycobacterial electron transport chain utilizes two terminal oxidases for the reduction of oxygen, namely the bc1-aa3 supercomplex and the cytochrome bd oxidase. The bc1-aa3 supercomplex is an energy-efficient terminal oxidase that pumps out four vectoral protons, besides consuming four scalar protons during the transfer of electrons from menaquinone to molecular oxygen. In the past few years, several inhibitors of bc1-aa3 supercomplex have been developed, out of which, Q203 belonging to the class of imidazopyridine, has moved to clinical trials. Recently, the crystal structure of the mycobacterial cytochrome bc1-aa3 supercomplex was solved, providing details of the route of transfer of electrons from menaquinone to molecular oxygen. Besides providing insights into the molecular functioning, crystal structure is aiding in the targeted drug development. On the other hand, the second respiratory terminal oxidase of the mycobacterial respiratory chain, cytochrome bd oxidase, does not pump out the vectoral protons and is energetically less efficient. However, it can detoxify the reactive oxygen species and facilitate mycobacterial survival during a multitude of stresses. Quinolone derivatives (CK-2-63) and quinone derivative (Aurachin D) inhibit cytochrome bd oxidase. Notably, ablation of both the two terminal oxidases simultaneously through genetic methods or pharmacological inhibition leads to the rapid death of the mycobacterial cells. Thus, terminal oxidases have emerged as important drug targets. In this review, we have described the current understanding of the functioning of these two oxidases, their physiological relevance to mycobacteria, and their inhibitors. Besides these, we also describe the alternative terminal complexes that are used by mycobacteria to maintain energized membrane during hypoxia and anaerobic conditions.

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“…However, at certain concentrations, thiols have the ability to produce oxidative species, such as OH•, leading to DNA breaks and other impairments in DNA molecules, which could further be connected with chromosome damage and cell apoptosis [74]. As DTT is often one of cell culture media components and can be added directly to the medium [75], studies have demonstrated that DTT lacks selectivity and spatial resolution [76] and leads to cellulose-anchored biofilm formation in Mycobacterium tuberculosis cultures, which contain metabolically active but drug-tolerant bacteria [77,78]. Importantly, in certain studies, while DTT has been implemented as a therapy-oriented approach or treatment of some syndromes and complications [63,79], its efficacy remains poorly understood [80].…”

Section: Current Insights Into the Dtt-induced Reductive Stressmentioning

confidence: 99%

“…Moreover, the concentration of DTT is closely related to DNA protection or DNA damage [74]. In addition, further investigations on its drug-tolerance and therapy as well as efficacy should also be highly warranted [63,[77][78][79][80]. 4 Oxidative Medicine and Cellular Longevity morphological abnormalities cannot be identified in some studies in spite of the presence of severe cardiomyopathy and mitochondrial dysfunction [88].…”

Section: Downregulationmentioning

confidence: 99%

Reductive Stress-Induced Mitochondrial Dysfunction and Cardiomyopathy

Tao

et al. 2020

Oxidative Medicine and Cellular Longevity

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The goal of this review was to summarize reported studies focusing on cellular reductive stress-induced mitochondrial dysfunction, cardiomyopathy, dithiothreitol- (DTT-) induced reductive stress, and reductive stress-related free radical reactions published in the past five years. Reductive stress is considered to be a double-edged sword in terms of antioxidation and disease induction. As many underlying mechanisms are still unclear, further investigations are obviously warranted. Nonetheless, reductive stress is thought to be caused by elevated levels of cellular reducing power such as NADH, glutathione, and NADPH; and this area of research has attracted increasing attention lately. Albeit, we think there is a need to conduct further studies in identifying more indicators of the risk assessment and prevention of developing heart damage as well as exploring more targets for cardiomyopathy treatment. Hence, it is expected that further investigation of underlying mechanisms of reductive stress-induced mitochondrial dysfunction will provide novel insights into therapeutic approaches for ameliorating reductive stress-induced cardiomyopathy.

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Reductive Stress: New Insights in Physiology and Drug Tolerance ofMycobacterium

Cited by 35 publications

References 152 publications

Glutathione S-Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish

Glutathione S-Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish

Terminal Respiratory Oxidases: A Targetables Vulnerability of Mycobacterial Bioenergetics?

Reductive Stress-Induced Mitochondrial Dysfunction and Cardiomyopathy

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